Convention suggests that the blood brain bar ier (BBB) prevents certain drugs and neurotoxins from gaining access to dopamine (DA) neurons in patients with Parkinson's disease (PD) unless a specific transport mech nism exists. However, we showed in animal, in vitro, and autopsy studies that the BB is dysfunctional in models of PD and patients. Animal and in vitro studies suggest d that products of activated microglial were responsible for this dysfunction. Ifbarri r function is compromised, the brain will be exposed to elements in the peripheral vasc lature. We hypothesize that BBB dysfunction williead to increased exposure 0 brain parenchyma to DA neurotoxins in the blood as well as peripheral immune syste mediators (T cells and monocytes) that will contribute to disease progression. Aim l'"II evaluate progressive DA neuron loss in mice with pre-existing DA lesions (induced b MPTP and LPS) for evidence of an increased entry of a tritium labeled, systemic By administered, DA neurotoxin (MPP+), and immune mediators. Aim 2 will assess fra tions from activated microglia (cell line and microglia isolated from DA lesioned mic for effects on endothelial cell (EC) monolayers (human cell line and mouse prim ry cultures) and changes in transport of DA toxins as well as transmigration of immu e mediators. These studies will also identify protein as well as ultrastructural cha ges (EM studies) in the tight junctions that create the BBB. We anticipate these stud es demonstrating that neuroinflammatory-mediated events affect p tein structure in tight junctions disrupting the BBB that leads to entry of peri heral vascular elements that contribute to further DA neuron loss and disease progressi n. These findings will systemat ically demonstrate, for the first time, that barrier d sfunction occurs in animal models of PD and identify potential mechanisms for this dy function. These findings would provide an entirely new hypothesis for progression pa hogenesis and identify new targets for therapeutic intervention in PD designed arou d affecting BBB integrity.